Inhibitors of RAS-effector protein interactions

Abstract

The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to compounds of Formula (I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.

The invention claimed is: 
     
       1. A compound of formula I, or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein,
 A 1  is selected from C 3-11 cycloalkyl optionally substituted by one or more R k , C 6-11  aryl optionally substituted by one or more R k , 3-15 membered heterocycloalkyl optionally substituted by one or more R k , and 5-15 membered heteroaryl optionally substituted by one or more R k ; 
 R k  is selected from hydrogen, hydroxyl, ═O, halogen, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkyl, O—C 1-6  alkyl, C 3-6  cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, benzyl, alkylheteroaryl, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR c S(═O) 2 NR c R d , —OR d , —SR d , —OC(═O)R d , —OC(═O)NR c R d , —OC(═O)OR d , —S(═O) 2 R d , —S(═O)R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 OR d , —S(═O)NR c R d , —OS(═O) 2 NR c R d , —S(═O) 2 NR c R d ; where said C 3-6  cycloalkyl, C 1-6  alkyl, 3-10 membered heterocycloalkyl, phenyl, benzyl, alkylheteroaryl, and O—C 1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, NR c R d , C 1-6  alkyl, O—C 1-6  alkyl, and phenyl; 
 R 2  is selected from —C(═O)NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NRS(═O) 2 NR c R d ; or a group of Formula III
   —(CR p R q ) f -J 2a -(CR u R v ) g -A 2a -((CR w R x ) h -J 2b -(CR y R z ) j -A 2b ) y   (III)
 
 
 wherein 
 R p , R q , R u  and R v , are independently selected from hydrogen, C 1-6  alkyl, C(O)NR c R d , C 3-7 cycloalkyl optionally substituted by one or more R b , (C 1-6 alkyl)phenyl optionally substituted by one or more R b , phenyl optionally substituted by one or more R b , (C 1-6  alkyl)C 3-7 cycloalkyl optionally substituted by one or more R b , 3-7 membered heterocycloalkyl optionally substituted by one or more R b , 3-7 membered (C 1-6 alkyl)heterocycloalkyl optionally substituted by one or more R b , 5-6 membered heteroaryl optionally substituted by one or more R b , and 5-6 membered (C 1-6 alkyl)heteroaryl optionally substituted by one or more R b ; 
 R p , R q , R u , R v  are independently selected from hydrogen and C 1-6  alkyl; 
   f, g, h  and  j  are independently selected from 0, 1, 2, 3 and 4; and  y  is selected from 0 and 1; 
 J 2a  is C(O)NR s1 , NR s1 C(O) and NR s1 ; where R s1  is selected from hydrogen, C 1-6  alkyl, C 3-7 cycloalkyl optionally substituted by one or more R b , (C 1-6 alkyl)phenyl optionally substituted by one or more R b , phenyl optionally substituted by one or more R b , (C 1-6 alkyl)C 3-7 cycloalkyl optionally substituted by one or more R b , 3-7 membered heterocycloalkyl optionally substituted by one or more R b , 3-7 membered (C 1-6  alkyl)heterocycloalkyl optionally substituted by one or more R b , 5-6 membered heteroaryl optionally substituted by one or more R b , and 5-6 membered (C 1-6 alkyl)heteroaryl optionally substituted by one or more R b ; 
 J 2b  is selected from O, S, C(O), CH 2 , C(O)NR s2 , NR s2 C(O) and NR s2 ; where R s2  is selected from hydrogen, C 1-6  alkyl, C 3-7 cycloalkyl optionally substituted by one or more R b , (C 1-6  alkyl)phenyl optionally substituted by one or more R b , phenyl optionally substituted by one or more R b , (C 1-6 alkyl)C 3-7 cycloalkyl optionally substituted by one or more R b , 3-7 membered heterocycloalkyl optionally substituted by one or more R b , 3-7 membered (C 1-6  alkyl)heterocycloalkyl optionally substituted by one or more R b , 5-6 membered heteroaryl optionally substituted by one or more R b , and 5-6 membered (C 1-6 alkyl)heteroaryl optionally substituted by one or more R b ; 
 each R b  is independently selected from hydroxyl, ═O, halogen, C 1-6  alkyl, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, OR d , 3-10 membered heterocycloalkyl, wherein said C 1-6  alkyl, C 3-6  cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NR c R d , C 1-6  haloalkyl, C 3-6  cycloalkyl, C 1-6  alkyl, phenyl and O—C 1-6  alkyl; 
 A 2a  is selected from C 3-11  cycloalkyl optionally substituted by one or more R t , 3-15 membered heterocycloalkyl optionally substituted by one or more R t , C 6-11  aryl optionally substituted by one or more R t , 5-15 membered heteroaryl optionally substituted by one or more R t ; 
 A 2b  is selected from C 3-11  cycloalkyl optionally substituted by one or more R t , 3-15 membered heterocycloalkyl optionally substituted by one or more R t , C 6-11  aryl optionally substituted by one or more R t , 5-15 membered heteroaryl optionally substituted by one or more R t;  and 
 R t  is selected from hydroxyl, ═O, halogen, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkyl, O—C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —C(O)C(═O)R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , —NR c C(═O)NR c R d , —NR c S(═O) 2 R d , —NR c S(═O) 2 NR c R d , —OR d , —SR d , —OC(═O)R d , —OC(═O)NR c R d , —OC(═O)OR d , —S(═O) 2 R d , —S(═O)R d , —OS(═O)R d , —OS(═O) 2 R d , —OS(═O) 2 OR d , —S(═O)NR c R d , —OS(═O) 2 NR c R d , —S(═O) 2 NR c R d ; where said C 3-6  cycloalkyl, C 1-6  alkyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, C 1-6  alkyl and O—C 1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, C(O)NR c R d , NR c R d , C 1-6  alkyl, and O—C 1-6  alkyl; and 
 
       wherein,
 each R c  is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6  haloalkyl, C 3-6  cycloalkyl, C 1-6  alkyl and O—C 1.6  alkyl; 
 each R d  is independently selected from hydrogen, hydroxyl, halogen, CN, C 1-6  haloalkyl, 3-7 membered heterocycloalkyl, C 3-6  cycloalkyl, C 1-6  alkyl, O—C 1-6  alkyl, C(═O)O(C 1-6 alkyl), 5-6 membered heteroaryl and phenyl, wherein said C 1-6  alkyl, O—C 1-6  alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 3 0.6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, ═O, halogen, CN, NH 2 , NHMe, NMe 2 , C 1-6  haloalkyl, C 3-6  cycloalkyl, C 6-11  aryl, C 1-6  alkyl and O—C 1-6  alkyl; or 
 R c  and R d , when attached to the same atom, together with the atom to which they are attached form a 3-10 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more R m ; and 
 R m  is selected from hydrogen, hydroxyl, ═O, halogen, C 1-6  alkyl, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, OR d , 3-10 membered heterocycloalkyl, 5-6 membered (C 1-6  alkyl)heterocycloalkyl 5-6 membered (C 1-6  alkyl)heteroaryl wherein said C 1-6  alkyl, C 3-6  cycloalkyl, 3-10 membered heterocycloalkyl, 5-6 membered (C 1-6  alkyl)heterocycloalkyl, and 5-6 membered (C 1-6  alkyl)heteroaryl are optionally substituted with one or more groups selected from hydroxyl, halogen, CN, NH 2 , NHMe, NMe 2 , C 1-6  haloalkyl, C 3-6  cycloalkyl, C 1-6  alkyl, phenyl, and O—C 1-6  alkyl. 
 
     
     
       2. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 1  is selected from C 6-11  aryl optionally substituted by one or more R k , 3-15 membered heterocycloalkyl optionally substituted by one or more R k , and 5-15 membered heteroaryl optionally substituted by one or more R k . 
     
     
       3. A compound according to  claim 1 , or a salt or solvate thereof, wherein R k  is selected from hydrogen, hydroxyl, ═O, halogen, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkyl, and O—C 1-6  alkyl; where said C 1-6  alkyl and O—C 1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, NR c R d , C 1-6  alkyl, O—C 1-6  alkyl, and phenyl. 
     
     
       4. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 1  is 
       
         
           
           
               
               
           
         
         where the phenyl and pyridyl rings are optionally substituted with one or more groups selected from C 1-3  alkyl and halogen. 
       
     
     
       5. A compound according to  claim 1 , or a salt or solvate thereof, wherein R 2  is selected from —C(═O)NR c R d , —N c  C(═O)R d  and a group of Formula III. 
     
     
       6. A compound according to  claim 1 , or a salt or solvate thereof, wherein R 2  is selected from a group of Formula III. 
     
     
       7. A compound according to  claim 1 , or a salt or solvate thereof, wherein J 2a  is selected from C(O)NR s1  and NR s1 C(O). 
     
     
       8. A compound according to  claim 1 , or a salt or solvate thereof, wherein the compound is of sub-formula Ic: 
       
         
           
           
               
               
           
         
         where A 1 , A 2a , R w , R x , J 2b , R y , R z , A 2b ,  h, j  and  y  are as defined in  claim 1 . 
       
     
     
       9. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 2a  is selected from C 3-11  cycloalkyl optionally substituted by one or more R t , 3-15 membered heterocycloalkyl optionally substituted by one or more R t , C 6-11  aryl optionally substituted by one or more R t , and 5-15 membered heteroaryl optionally substituted by one or more R t . 
     
     
       10. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 2a  is selected from phenyl optionally substituted by one or more R t , tetrahydropyran optionally substituted by one or more R t , piperazine optionally substituted by one or more R t , piperidine optionally substituted by one or more R t , furan optionally substituted by one or more R t , and oxazole optionally substituted by one or more R t . 
     
     
       11. A compound according to  claim 1 , or a salt or solvate thereof, wherein  y  is 0. 
     
     
       12. A compound according to  claim 1 , or a salt or solvate thereof, wherein  y  is 1. 
     
     
       13. A compound according to  claim 1 , or a salt or solvate thereof, wherein J 2b  is CH 2 . 
     
     
       14. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 2b  is selected from phenyl optionally substituted by one or more R t , 5-6 membered heterocycloalkyl optionally substituted by one or more R t , and a 5-6 membered heteroaryl optionally substituted by one or more R t . 
     
     
       15. A compound according to  claim 1 , or a salt or solvate thereof, wherein R t  is selected from hydroxyl, ═O, halogen, C 1-6  alkyl, O—C 1-6  alkyl, C 3-6  cycloalkyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, —C(═O)R d , —C(═O)OR d , —C(═O)NR c R d , —NR c R d , —NR c C(═O)R d , —NR c C(═O)OR d , and —NR c C(═O)NR c R d ; where said C 3-6  cycloalkyl, C 1-6  alkyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, C 1-6  alkyl and O—C 1-6 alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, ═O, CN, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, C(O)NR c R d , NR c R d , C 1-6  alkyl, and O—C 1-6  alkyl. 
     
     
       16. A compound according to  claim 1 , or a salt or solvate thereof, wherein R 2  is selected from 
       
         
           
           
               
               
           
         
       
     
     
       17. A compound, or a salt or solvate thereof, selected from:
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 Oxazole-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 Oxazole-2-carboxylic acid [(R)-7-(pyridin-3-ylmethoxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 Oxazole-2-carboxylic acid [(R)-7-(1H-pyrazol-4-ylmethoxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 Oxazole-2-carboxylic acid [(R)-7-(1-methyl-piperidin-4-ylmethoxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [(R)-7-(4-methoxy-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid ((R)-7-phenethyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [(R)-7-(4-chloro-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-oxazole-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 1-methyl-piperidine-4-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 Tetrahydro-pyran-4-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-dimethylamino-propionamide; 
 Oxazole-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[4-(3-dimethylamino-propoxy)-benzyl]-amide; 
 (4-{[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(oxazole-2-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester; 
 Oxazole-2-carboxylic acid (4-aminomethyl-benzyl)-((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 Oxazole-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(1-benzyl-piperidin-4-ylmethyl)-amide; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(tetrahydro-pyran-4-ylmethyl)-amine; 
 Oxazole-2-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(1-benzyl-piperidin-4-yl)-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [(R)-7-(5-chloro-pyridin-3-ylmethoxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid ((R)-7-benzylamino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-carboxylic acid [(R)-7-(5-chloro-pyridin-2-ylmethoxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-{2-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-2-phenyl-ethyl}-pyrrolidin-2-one; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-indan-1-yl-amine; 
 C-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methylamine; 
 2-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-N-methyl-2-phenyl-acetamide; 
 2-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-N-methyl-2-phenyl-acetamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (4-amino-cyclohexyl)-amide; 
 3-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (1H-imidazol-2-yl)-amide; 
 3-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1-pyridin-2-yl-imidazolidine-2,4-dione; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid [4-(2-amino-acetylamino)-cyclohexyl]-amide; 
 3-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1-piperidin-4-yl-imidazolidine-2,4-dione; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(1-methyl-piperidin-4-ylmethyl)-amine; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid 3-(4-methyl-piperazin-1-ylmethyl)-benzylamide; 
 (7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone; 
 (7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-yl)-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-methanone; 
 N-{4-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-cyclohexyl}-2-dimethylamino-acetamide; 
 1-{2-[4-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperazin-1-yl]-ethyl}-1H-pyridin-2-one; 
 N-{4-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-(2H-pyrazol-3-ylmethyl)-amino]-cyclohexyl}-2-dimethylamino-acetamide; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[3-(4-methyl-piperazin-1-yl)-benzyl]-amine; 
 1-(7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(1-methyl-piperidin-4-yl)-urea; 
 4-methyl-piperazine-1-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 3-(7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-1-methyl-1-(1-methyl-piperidin-4-yl)-urea; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(4-methyl-piperazin-1-ylmethyl)-benzamide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-2-(1-methyl-piperidin-4-yl)-acetamide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-2-piperidin-4-yl-acetamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid 4-morpholin-4-ylmethyl-benzylamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid 3-morpholin-4-ylmethyl-benzylamide; 
 4-(4-{[(7-benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl)-amino]-methyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester; 
 7-benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid 4-piperazin-1-ylmethyl-benzylamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (pyridin-4-ylmethyl)-amide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-2-pyridin-4-yl-acetamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (morpholin-3-ylmethyl)-amide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-2-pyridin-3-yl-acetamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (2-oxo-piperidin-4-ylmethyl)-amide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (2-fluoro-pyridin-4-ylmethyl)-amide; 
 N-((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-2-(3,5-dimethyl-1H-pyrazol-4-yl)-acetamide; 
 7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (1H-pyrazol-4-ylmethyl)-amide; 
 Piperidine-4-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-4-yl-amine; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-morpholin-3-ylmethyl-amine; 
 1-Carbamoylmethyl-piperidine-4-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 
 1-{4-[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-piperidin-1-yl}-ethanone; 
 5-{[((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-methyl}-piperidin-2-one; 
 ((R)-7-Benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-ylmethyl-amine; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(3,4-difluoro-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(3-methyl-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(4-methyl-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(3-chloro-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(4-chloro-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(4-fluoro-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; 
 1-Methyl-piperidine-4-carboxylic acid [(R)-7-(2-methyl-benzyloxy)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl]-amide; and 
 1-Furan-2-ylmethyl-piperidine-4-carboxylic acid ((R)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide. 
 
     
     
       18. A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. 
     
     
       19. A combination comprising a compound according to  claim 1  and a further therapeutically active agent. 
     
     
       20. A compound according to  claim 1 , or a salt or solvate thereof, wherein A 1  is phenyl optionally substituted by one or more R k .